Cell death plays an important role in development, tissue homeostasis, and degenerative diseases. Two major forms of cell death have been described: apoptosis and necrosis. Apoptosis, also called programmed cell death, is an energy-driven process by which a cell actively destroys itself in response to extracellular signals or developmental cues, whereas necrosis has been considered a passive process in which a cell dies as a result of bioenergetic catastrophe. Apoptosis is characterized by the ordered cellular degradation of proteins and organelles, maintenance of plasma membrane integrity, and non-inflammatory phagocytosis of the dying cell (Adams 2003; Wang 2001). During necrosis, cells swell rapidly and lose the integrity of their plasma membrane, releasing cellular contents into the extracellular environment, and triggering an acute inflammatory response. Necrosis has traditionally been considered an unregulated form of cell death, and has been well characterized in a wide range of pathologic states including ischemia, trauma, and infection (Majno and Joris 1995; Kanduc et al. 2002).
A great deal of recent attention has focused on the role of apoptosis in normal development and various disease processes. Most if not all cancer cells have defects in the normal control of apoptosis. The first characterized example of this is the 14:18 chromosomal translocation found in patients with follicular lymphoma that juxtaposes the immunoglobulin enhancer with the anti-apoptotic gene bcl-2 (Tsujimoto et al. 1984). Enhanced expression of Bcl-2 provides resistance to apoptosis by suppressing the activation of the proapoptotic Bcl-2 related proteins Bax and Bak. Bax and Bak are essential in apoptosis initiated from both mitochondria and the endoplasmic reticulum (ER). Cells lacking both Bax and Bak are resistant to apoptosis induced by developmental cues, signal transduction through death receptors, growth factor withdrawal, and ER stress (Lindsten et al. 2000; Wei et al. 2001; Zong et al. 2001, Cheng et al. 2001; Degenhardt et al. 2002b; Scorrano et al. 2003; Zong et al. 2003).
Despite the role of Bcl-2 as an anti-apoptotic protein, follicular lymphoma cells are sensitive to treatment with DNA alkylating drugs in vivo (Lister 1991).
Although there have been advancements in the treatment of cancer a hallmark of many cancers is that the treatments fail to work after a period of time as the cancer cells become resistant to the treatment. Much of this resistance is due to inhibition of the apoptosis pathway due to genetic mutations in the cell. However, cells can still die by other processes including necrosis. Thus, there is a need to identify compounds that can act as anti-cancer agents. There is also a need to identify anti-cancer agents that are able to kill cancer cells that do not die by apoptosis.